Wang Zhe, Xu Pengwei, Guo Shu-Min, Daniliuc Constantin G, Studer Armido
Organisch-Chemisches Institut, Universität Münster, Münster, Germany.
Nature. 2025 May 21. doi: 10.1038/s41586-025-09019-6.
Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound's backbone structure. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Instead of constructing a heteroarene classically from basic building blocks, structural variants are readily accessible directly starting from a lead compound or approved pharmacophore. Here we present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Reactions proceed through ring-opened oximes as intermediates. These ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzoxazoles. The compound classes obtained through these methods-indazoles, benzisoxazoles, benzimidazoles and benzoxazoles-are biologically relevant moieties found as substructures in natural products and pharmaceuticals. The procedures introduced substantially enlarge the methods portfolio in the emerging field of skeletal editing.
骨架编辑包括化合物的结构重组。这种编辑可以通过原子交换、原子插入、原子删除或化合物骨架结构的重组来实现。在药物开发活动的后期进行，骨架编辑能够使现有的药效团多样化，提高药物开发的效率。与传统上从基本构建单元构建杂芳烃不同，结构变体可以直接从先导化合物或已批准的药效团轻松获得。在这里，我们展示了在吲哚的C2位置进行碳到氮的原子交换，通过吲哚杂芳烃核心的氧化裂解和随后的闭环反应生成吲唑。反应通过开环肟作为中间体进行。这些环解构中间体也可以转化为苯并咪唑，从而实现整体的碳到氮原子交换以及伴随的骨架重组。相同的结构转化策略同样适用于苯并呋喃，可生成苯并异恶唑或苯并恶唑。通过这些方法获得的化合物类别——吲唑、苯并异恶唑、苯并咪唑和苯并恶唑——是天然产物和药物中作为子结构发现的具有生物学相关性的部分。所介绍的方法极大地扩展了骨架编辑这一新兴领域的方法组合。
